Author ORCID Identifier
0000-0002-4643-7078
Date of Graduation
5-2018
Document Type
Dissertation (PhD)
Program Affiliation
Genes and Development
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Guillermina Lozano
Committee Member
Swathi Arur
Committee Member
Richard Behringer
Committee Member
Anil Sood
Committee Member
William Mattox
Abstract
Altered DICER1 protein levels are associated with developmental disorders, infertility, macular degenerative blindness, aging, and cancer in humans. Recently, post-translational regulation of Dicer1 via phosphorylation has been described in C. elegans. Oscillation of Dicer1 phosphorylation to regulate its activity is essential for germ cell development and embryogenesis in worms. These observations led us to posit that Dicer1 protein levels and activity are under tight regulation for normal mammalian homeostasis. To test whether phosphorylation of Dicer1 regulates its activity in mammals, I generated phospho-mimetic knock-in mouse models by replacing Serines 1712 and 1836 with Aspartic acids individually or together (dual phosphorylation). Dicer1 functions are impaired by phosphorylation at Ser1836, and further augmented by Ser1712 phosphorylation. Constitutive Dicer1 phosphorylation at Ser1836 leads to highly penetrant post-natal lethality, and accelerates aging and causes infertility in survivors. Homozygosity of dual phosphorylated Dicer1 leads to a hypermetabolic phenotype in MEFs and mice, while heterozygosity is sufficient to promote tumor development and dissemination in two independent tumor models. I have identified a phospho-Dicer1 specific miRNA signature that is strongly associated with metabolic and oncogenic pathways. These data identify constitutive phosphorylation of Dicer1 as a driver of pathologies in mammals, with the phenotypes in mice resembling the spectrum of human diseases associated with dysregulated DICER1.
Keywords
Dicer, miRNA, Phosphorylation, ERK, KRas, p53, Aging, Cancer, Metabolism